Cancer is the second most common cause of death in the United States and European Union (National Vital Statistics Reports, Vol. 60, No. 4, 2012) and the first most common cause of death among persons aged 45 to 64, for both men and women, in the European Union. The estimated cancer prevalence in the United States as of Jan. 1, 2008 was 5,506,000 cases of invasive tumors for males and 6,452,000 cases for females.
Cancer vaccines are under investigation, with some in Phase III efficacy studies (Rosenberg et al., Nat Med., 10:909 (2004), Johnson et al., Expert Rev Anticancer Ther., 9:67 (2009)3,4). Several cancer vaccines are directed against solid tumors—melanoma, prostate, lung, breast and colorectal cancers. Two high risk populations will particularly benefit from preventive anti-cancer vaccines: the patients with surgically removed tumors belonging to cancer types that are known to have high metastatic potential (e.g., ovarian or some types of breast cancer), and also carriers of known mutations, associated with higher cancer risk (e.g., mutations in BRCA1 and BRCA2 genes for breast and ovarian cancers, RAD51 gene for ovarian cancer, etc.). Selective preventive vaccination of high-risk cohort of women is an important public health task.
p62 is a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene.
p62 was identified as 62-kDa protein that was binding the src homology 2 (SH2) domain of tyrosine kinase Lckp56 in a phosphotyrosine-independent manner (Park et al., Proc Natl Acad Sci USA., 92:12338 (1995)). The primary sequence of p62 is known (Joung et al., Proc Natl Acad Sci USA., 93:5991, (1996)), and was shown to bind ubiquitin (Vadlamudi et al., J. Biol. Chem., 271:20235 (1996)). The DNA sequence of human p62, Homo sapiens sequestosome 1 (SQSTM1), transcript variant 1, mRNA, can be accessed at NCBI Reference Sequence: NM_003900.4. The amino acid sequence of human p62, Sequestosome-1 isoform 1 [Homo sapiens], can be accessed at NCBI Reference Sequence: NP 003891.1. p62 has homology neither with ubiquitin C-terminal hydrolases nor with the S5a subunit of the 26 S proteasome complex, the only proteins known to bind to ubiquitin noncovalently. These results suggested that p62 belongs to a new class of ubiquitin-binding proteins.
p62 is a component of inclusion bodies found in protein aggregation diseases in the brain and liver: p62 is sequestered into cytoplasmic inclusion bodies, called sequestosomes. These p62-containing protein aggregates are degraded by autophagy. It was suggested that this function of p62 may have a protective effect on huntingtin-induced cell death (Bjorkoy et al., J Cell Biol., 171:603 (2005)). Mutations in p62 gene have been associated with sporadic and familial Paget disease (Jenny Chung et al., Semin Arthritis Rheum., 41:619 (2012)), a metabolic bone disease.